The immune system of a mammal often provides the first line of defense against pathogenic organisms, as well as against tumors. The immune system recognizes antigens expressed by tumor cells or pathogens as foreign, i.e., “non-self”. Upon recognition of a non-self antigen, an immune response is mounted against the antigen, resulting in antibodies and/or cytolytic T cells which recognize the antigen. The immune response of a mammal is also responsible for allergy (to antigens known as allergens) and autoimmune disease, which results from inappropriate recognition of host proteins as non-self.
The process by which the mammalian immune system recognizes and reacts to foreign or alien materials is a complex one. An important facet of the system is the T cell response. This response requires that T cells recognize and interact with complexes of cell surface molecules, referred to as human leukocyte antigens (“HLA”), or major histocompatibility complexes (“MHCs”), and peptides. The peptides are derived from larger molecules which are processed by the cells which also present the HLA/MHC molecule. The interaction of T cells and complexes of HLA/peptide is restricted, requiring a T cell specific for a particular combination of an HLA molecule and a peptide. Another mechanism exists for presentation of non-peptide antigens (such as lipids, glycolipids and carbohydrates) to T cells. This mechanism involves the formation of a complex of the non-peptide antigen and CD1 proteins. If a specific T cell is not present, there is no T cell response even if its partner complex is present. Similarly, there is no response if the specific complex is absent, but the T cell is present. These mechanisms are involved in the immune system's response to foreign materials, in autoimmune pathologies, and in responses to cellular abnormalities.
It has been demonstrated that cytotoxic T lymphocytes provide an effective response against tumor cells. Tumor cells express tumor associated genes. The protein expression products of these genes are processed into peptides which, in turn, are presented by HLA/MHC on cell surfaces, which can lead to lysis of the tumor cells by specific CTLs. The genes are said to code for proteins which are “tumor rejection antigen precursors”, and the peptides derived therefrom are referred to as “tumor rejection antigens”. Therefore, immunization which increases host cytotoxic T lymphocytes specific for one or more tumor rejection antigens can reduce tumor load in the host. CTL involvement in other desirable immune responses (e.g. against antigens of pathogens) as well as in undesirable immune responses (e.g. against allergens, self antigens and antigens associated with transplanted tissue grafts) is also well known.
Several steps are required for the generation of a specific T cell response, starting with antigen processing and presentation of antigenic peptides by MHC on antigen presenting cells (APCs), followed by T cell priming from signals transmitted through the T cell receptor and through co-stimulatory molecules, such as CD28 and CD40 ligand, resulting in the clonal expansion of T cells.
Dendritic cells (DCs) are potent antigen presenting cells which efficiently stimulate immune recognition of presented peptides. Activation of naive T cells in lymph nodes is mediated exclusively by dendritic cells. A major weakness of current DC immunization approaches is the inability to deliver the DCs directly from blood to secondary lymphoid tissues (including lymph nodes) throughout the body where selectin ligands on endothelial cells are required for homing of blood-borne leukocytes. Thus there is a need to have improved methods and compositions for stimulating immune responses against pathogenic organisms, cellular abnormalities including tumors, and the like.
There is also a need to have improved methods and compositions for reducing inappropriate immune responses, such as found in allergy and autoimmune disease. Reduction of host immune responses is also desirable to reduce allograft transplant rejection by the host.